Ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) is a potent neuroleptic agent useful in the treatment of various disorders including schizophrenia, anxiety and pain. It is currently marketed under the proprietary name of Geodon. Ziprasidone hydrochloride is known to exist in three crystalline forms; namely, the monohydrate, hemihydrate and anhydrous form as disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925, both of which are herein incorporated by reference. U.S. Pat. No. 5,312,925 states that ziprasidone hydrochloride monohydrate is hygroscopically stable, thus alleviating potential problems due to weight changes of the active pharmaceutical ingredient during the final formulation process. Nevertheless a very low aqueous solubility is observed for this crystalline form.
Canadian patent 2,252,898 attempts to overcome some of the deficiencies of the prior art, especially the poor aqueous solubility of ziprasidone hydrochloride monohydrate, by formation of various mesylate hydrate salts.
In U.S. Pat. No. 6,150,366 the poor aqueous solubility is purportedly increased by controlling, by various methods, the mean particle size of the crystalline ziprasidone free base or ziprasidone hydrochloride to a mean particle size equal to or less than about 85 μm.
U.S. Pat. No. 5,935,960 describes another attempt to overcome the poor aqueous solubility of ziprasidone hydrochloride by formation of a pro-drug of ziprasidone, specifically 1-[2-(6-chloro-2,3-dihydro-2-oxo-1H-indol-5-yl)ethyl]-4-[imino(2-mercaptophenyl)methyl]piperazine or one of its pharmaceutically acceptable salts, for instance the dihydrochloride.
Canadian patent 2,245,269 describes numerous compositions comprising of solid spray dried dispersions of sparingly water soluble drugs, including ziprasidone free base, and hydroxypropylmethylcellulose acetate succinate. Again, the form obtained purportedly provides increased aqueous solubility and/or bioavailability.
Therefore, a method which produces an improved form of ziprasidone hydrochloride in high yields and purity, and helps to overcome some of the deficiencies of the known forms is desired.